1. Field of the Invention
This invention relates to the field of controlled release delivery of therapeutic peptides and to compositions and methods useful for controlled release delivery of therapeutic peptides covalently modified with one or more lipophilic or amphiphilic molecules.
2. Description of the Related Art
Peptides, alternatively referred to as oligopeptides, polypeptides and proteins, have been widely used as therapeutic agents. The peptides may be conveniently produced by recombinant DNA technology or may be synthesized by well-established peptide synthesis technology. However, many peptides are susceptible to enzymatic degradation and have a very short in vivo circulation half-life. Therefore, most peptide medicines have been administered by injection, typically multiple times per day. It would be extremely beneficial if such peptides could be delivered in a controlled manner for extended periods of time to improve safety, efficacy and patient compliance.
Biodegradable polymers have been used for sustained delivery of therapeutic peptides. The peptide is generally incorporated into the polymeric composition and formed into desired shapes such as rods, wafers and microparticles outside of the body. These solid compositions can then be inserted into the body through an incision or injection. Alternatively and preferably, some of the polymeric compositions can be injected into the body as a liquid polymeric composition to form an implant in situ. Injectable liquid biodegradable polymeric compositions for in situ forming implants to deliver drugs in a controlled manner are described in the patent literature. The following references are believed to be representative in this area and are incorporated herein by reference: U.S. Pat. Nos. 6,565,874; 6,528,080; RE37,950; 6,461,631; 6,395,293; 6,355,657; 6,261,583; 6,143,314; 5,990,194; 5,945,115; 5,792,469; 5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950; 5,702,716; 5,681,873; 5,599,552; 5,487,897; 5,340,849; 5,324,519; 5,278,202; 5,278,201; and 4,938,763. As described therein, a bioactive agent is dissolved or dispersed in a biodegradable polymer solution in a biocompatible organic solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent dissipates into the surrounding aqueous environment, and the polymer precipitates to form a solid or gel depot from which the bioactive agent is released over a long period of time as the polymer degrades. The use of such a delivery system was exemplified in the delivery of leuprolide acetate to treat advanced prostate cancer (Eligard™). Notwithstanding some success, those methods have not been entirely satisfactory for a large number of peptides that may be effectively delivered by such an approach.
For many therapeutic peptides, acylation and/or degradation of the peptides encapsulated in poly(DL-lactide-co-glycolide) microspheres have been observed during the release process [e.g., Na D H, Youn Y S, Lee S D, Son M O, Kim W A, DeLuca P P, Lee K C. J Control Release. 2003; 92(3):291-9]. The nucleophilic functional groups on peptides can not only react with the biodegradable polymer, but also can catalyze the degradation of the biodegradable polymer. It was also found that the acylation and/or degradation could occur much faster in polymer solution than in the solid state. For example, when octreotide acetate was mixed with 50/50 poly(DL-lactide-co-glycolide) having a carboxy terminal group solution in NMP, more than 80% of octreotide was acylated and/or degraded within 24 hours. The interaction/reaction between the peptide and polymer or its degradation products can occur during formulation, storage and administration. Therefore, in order to maintain the stability of the formulations, the peptide is typically supplied in a separate syringe while the rest of the components are packed in another syringe. The contents in the syringes are mixed just before use. However, because of the viscous nature of the polymer formulations, it is often difficult to mix the contents in two separated syringes by end users. The uniformity of the formulations prepared by the end user may vary significantly, contamination may also occur and, thus, the quality of the treatment can be compromised significantly. Furthermore, the in-situ formation of the solid implant from the injectable liquid polymer formulation is a slow process. Typically the solvent dissipation/diffusion process can take a few hours to several days or even longer depending on the solvent used. During this period, the presence of organic solvent could promote the interaction/reaction between peptide and polymer or its degradation products.
In addition, during the formation of the implant, the rate of diffusion of the peptide from the coagulating polymeric composition may be much more rapid than the rate of release that occurs from the subsequently formed solid implant. This initial “burst” release of peptide during implant formation may result in the loss or release of a large amount of the therapeutic peptides. If the peptide is particularly toxic or has a narrow therapeutic window, this initial release or burst is likely to lead to toxic side effects and may damage adjacent tissues. Therefore, the slow formation process of solid implant and the instability of the bioactive agents and/or excipients represent a very significant challenge to use this type of formulations for sustained release delivery of therapeutic peptides.
Covalent modification of peptides with lipophilic molecules, such as fatty acids, has been described to improve therapeutic efficacy by increasing circulating half-life in vivo through binding to albumin. [EP0708179-A2, EP0699686-A2, U.S. Pat. No. 6,268,343, Knudsen L B, Nielsen P F, Huusfeldt P O, Johansen N L, Madsen K, Pedersen F Z, Thogersen H, Wilken M, Agerso H. Potent derivatives of glucagon:like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000, 43(9):1664-9; Kurtzhals P, Havelund S, Jonassen I, Kiehr B, Larsen U D, Ribel U, Markussen J. Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo. Biochem J. 1995; 312 (3):725-31, and references cited therein]. Although the lipophilically modified peptides showed prolonged action in vivo compared with the native peptides, the plasma residence time of the modified peptides is limited by its binding affinity to albumin. One successful example is an acylated insulin (Detemir) which has a circulation half-life of 10.2±1.2 h. [Havelund S, Plum A, Ribel U, Jonassen I, Vølund A, Markussen J and Kurtzhals P, Pharmaceutical Research, 2004; 21 (8), 1498-1504]. This product has been approved for injection to treat patients with type I diabetes. However, it still needs to be administered to patients everyday. Therefore, there is a great need for a stable composition in which the rate of delivery of certain peptides can be more readily controlled, especially for a peptide that requires sustained release over a long period of time.